Our major objective is to elucidate the mechanisms of tumor promotion, which appears to be a component of carcinogenesis in general, and its inhibition by various agents, with special reference to the role of cyclic nucleotides. We have shown that the promoter phorbol myristate acetate (PMA) produced a marked and prolonged stimulation of cyclic GMP synthesis in mouse epidermis. We will study: 1) The mechanisms responsible for this stimulation, which may involve release of unsaturated fatty acids and increased prostaglandin synthesis, and 2) the possible effects of increased cGMP, such as changes in chromosomal protein phosphorylation. We have shown that butyric acid inhibits promotion, induces beta-adrenergic hormone receptor synthesis and facilitates the coupling of beta-receptors to adenyl cyclase in mouse epidermis. The uncoupling effect of PMA is overcome by butyric acid. The role of uncoupling in tumor promotion will be clarified by testing other uncoupling agents such as filipin and amphotericin B as promoters. The mechanism of butyric acid inhibition of promotion may involve its effect on the coupling reaction or on altered histone acetylation which will also be examined. Agents which inhibit cGMP stimulation and protein phosphorylation will be tested as promotion inhibitors.